ArticleJAMA network open2022
Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality.
Article in JAMA network open, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- Cross-ancestry genome-wide association studies of liver function biomarkers uncover pleiotropic variants, systemic disease links and therapeutic targets.Genome medicine · 2026Pooled it
- Steatotic liver disease in Latin America: current views and perspectives.Nature reviews. Gastroenterology & hepatology · 2026Review
- Alcohol-aware risk stratification and subtype-specific care pathways across metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction and alcohol-associated liver disease, and alcohol-associated liver disease.Clinical and molecular hepatology · 2026Review
- Genetic and genomic insights across the steatotic liver disease spectrum.Clinical and molecular hepatology · 2026Review
- Global epidemiology of metabolic and alcohol-associated liver disease: risk factors, natural history and clinical implications.Nature reviews. Gastroenterology & hepatology · 2026Review
- Editorial: Two Common Risks, One Greater Harm-Diabetes and Alcohol in Steatotic Liver Disease.Alimentary pharmacology & therapeutics · 2026Article
- Exposure to Poly- and Perfluoroalkyl Substances and Risk of Hepatocellular Carcinoma in Male Patients with Cirrhosis Related to Hepatitis C Virus Infection.Liver cancer · 2026Article
- Germline mutations and somatic mosaicism in steatotic liver diseases and related liver carcinogenesis.Nature reviews. Gastroenterology & hepatology · 2026Review
- Accelerating discovery of cancer causes for prevention in the era of rising early-onset cancers.Cell · 2026Review
- Risk-stratified surveillance for hepatocellular carcinoma.Hepatology communications · 2026Review
- Ferroptosis: The Demise of Cells Through Phospholipid Peroxidation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Novel biomarkers for alcohol-associated liver disease and their implications across clinical settings.Clinical and molecular hepatology · 2026Review
- Genetic and non-genetic drivers of histological progression and regression in MASLD.Journal of hepatology · 2026Article
- Linkage disequilibrium score regression identifies genetic correlations between hepatocellular carcinoma and clinically relevant traits.International journal of cancer · 2026Article
- Article
- Met-ALD and ALD- Does Differentiating These Impact Management and Clinical Outcomes?Current hepatology reports · 2025Article
- High inherited risk predicts age-associated increases in fibrosis in patients with MASLD.Journal of hepatology · 2025Article
- High-Risk PNPLA3 rs738409 Genotype Is Associated with Higher Concentrations of CCL2 in Liver Transplant Candidates with Alcoholic End-Stage Liver Disease.Medicina (Kaunas, Lithuania) · 2025Article
- Polymorphism's MBOAT7 as Risk and MTARC1 as Protection for Liver Fibrosis in MASLD.International journal of molecular sciences · 2025Article
- Gene-based therapies for steatotic liver disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
Importance: Alcohol drinking and obesity are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC), but the risk is not uniform among people with these risk factors. Genetic variants, such as I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, may play an important role in modulating cirrhosis and HCC risk. Objective: To investigate the joint associations of the PNPLA3 I148M variant, alcohol intake, and obesity with the risk of cirrhosis, HCC, and liver disease-related mortality. Design, Setting, and Participants: This prospective cohort study analyzed 414 209 participants enrolled in the UK Biobank study from March 2006 to December 2010. Participants had no previous diagnosis of cirrhosis and HCC and were followed up through March 2021. Exposures: Self-reported alcohol intake (nonexcessive vs excessive), obesity (body mass index ≥30 [calculated as weight in kilograms divided by height in meters squared]), and PNPLA3 I148M variant status (noncarrier, heterozygous carrier, or homozygous carrier) from initial assessment. Main Outcomes and Measures: The primary outcomes were incident cirrhosis and HCC cases and liver disease-related death ascertained from inpatient hospitalization records and death registry. The risks were calculated by Cox proportional hazards regression models. Results: A total of 414 209 participants (mean [SD] age, 56.3 [8.09] years; 218 567 women [52.8%]; 389 452 White race and ethnicity [94.0%]) were included. Of these participants, 2398 participants (0.6%) developed cirrhosis (5.07 [95% CI, 4.87-5.28] cases per 100 person-years), 323 (0.1%) developed HCC (0.68 [95% CI, 0.61-0.76] cases per 100 person-years), and 878 (0.2%) died from a liver disease-related cause (1.76 [95% CI, 1.64-1.88] cases per 100 person-years) during a median follow-up of 10.9 years. Synergistic interactions between the PNPLA3 I148M variant, obesity, and alcohol intake were associated with the risk of cirrhosis, HCC, and liver disease-related mortality. The risk of cirrhosis increased supramultiplicatively (adjusted hazard ratio [aHR], 17.52; 95% CI, 12.84-23.90) in individuals with obesity, with excessive drinking, and who were homozygous carriers compared with those with no obesity, with nonexcessive drinking, and who were noncarriers. Supramultiplicative associations between the 3 factors and risks of HCC were found in individuals with 3 risk factors (aHR, 30.13; 95% CI, 16.51-54.98) and liver disease-related mortality (aHR, 21.82; 95% CI, 13.78-34.56). The PNPLA3 I148M variant status significantly differentiated the risk of cirrhosis, HCC, and liver disease-related mortality in persons with excessive drinking and obesity. Conclusions and Relevance: This study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with increased risk of cirrhosis, HCC, and liver disease-related death in the general population. The PNPLA3 I148M variant status may help refine the risk stratification for liver disease in persons with excessive drinking and obesity who may need early preventive measures.
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